Ozone is a major component of urban air pollution known to affect lung function, increase airway inflammation, and cause asthma exacerbations. Studies have reported a higher prevalence of inflammatory lung disease in women than men, but the mechanisms underlying these disparities are still unknown. Although the female lung, as compared to the male lung, is exposed to increased levels of estrogen and progesterone from both physiological and environmental sources, it is not known whether the combination of sex hormones and ozone can affect lung health. In this context, high levels of ozone and female gender are negative prognostic indicators for increased morbidity and mortality from chronic respiratory disease. The overall objectives of this K01 proposal are to provide additional training and laboratory expertise to the candidate, while she investigates mechanisms of ozone-induced inflammation in the male and female lung. The candidate is a well-qualified junior scientist with a strong track record of commitment to academic research. She has previously engaged in a wide variety of research projects, ranging from endocrinology and biochemistry to immunology and lung physiology, and she has demonstrated productivity and potential for independence. Her long-term career goal is to develop into an independent and productive scientist who investigates lung disease-relevant research with a creative and scientifically rigorous methodology. Through an integrated approach, this project will promote the candidate's scientific and career development with guidance from senior and experienced mentors, a scientific advisory committee comprised of experts in various aspects of the proposed work, and additional academic and hands-on training to acquire new research expertise. The Pennsylvania State University College of Medicine offers a unique environment to promote the success of the candidate, including a financial commitment and protection of research time, senior faculty with expertise in the research area, a collaborative and nurturing environment, and access to specialized resources, equipment, and facilities necessary to complete the project. The candidate is a faculty member of the Departments of Pediatrics and Biochemistry and Molecular Biology, where she has access to specialized expertise in the areas of lung disease research from basic and clinical investigators of diverse backgrounds. The central hypothesis of the proposed research plan is that both male and female sex hormones modulate ozone-induced inflammatory responses in the lung. Through a multidisciplinary approach, this proposal will test this hypothesis via the following aims: 1) to characterize sex differences in lung function and inflammation in response to ozone exposure, 2) to determine the role of sex hormones in ozone-induced lung inflammation, and 3) to evaluate the effects of ozone and sex hormones in asthmatic inflammation. Although previous clinical studies have indicated that the hormonal status can affect asthma exacerbations in women, this is the first study to examine the specific roles of male and female sex hormones in ozone-induced inflammation in the lungs of both normal and asthmatic mice. Together, the proposed studies will promote the scientific development of the candidate and increase the understanding of the role of sex hormones in the inflammatory response to a major air pollutant. As ambient ozone levels are anticipated to rise with climate change, ozone-related asthma emergency room visits are expected to increase. Therefore, an improved understanding of the role of sex hormones in the pathogenesis of asthmatic inflammation is of high clinical significance and will open the door for discovery of new gender specific therapeutic targets.